ARTEMIDA Trial (A Randomized Trial of Efficacy, 12 Months International Double-Blind Actovegin): A Randomized Controlled Trial to Assess the Efficacy of Actovegin in Poststroke Cognitive Impairment

Abstract

Background and purpose: Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke.

Methods: This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version at 6 months.

Results: Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version was -6.8 for Actovegin and -4.6 for placebo; the estimated treatment difference was -2.3 (95% confidence interval, -3.9, -0.7; P=0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo.

Conclusions: Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01582854.

Keywords: Actovegin; post-stroke cognitive impairment; stroke; vascular dementia.

Figure 1.

Patient flow diagram. The numbers presented are as treated. There were 2 patients who were randomized to the placebo group but received an incorrect kit, which after unblinding was determined to have contained Actovegin. Those patients are included as randomized for the intent-to-treat (ITT) analyses (placebo group) and as treated for the safety analyses (Actovegin group). More than 1 reason for discontinuation could have been selected.

Figure 2.

Analysis of the effect of Actovegin and placebo on Alzheimer’s Disease Assessment Scale, cognitive subscale, extended version (ADAS-cog+). A, Change in ADAS-cog+ score from baseline over the course of the study in the intent-to-treat (ITT) population. B, Analysis of ADAS-cog+ responders in the ITT population. A responder was defined as demonstrating an improvement of ≥4 points on the ADAS-cog+ scale using observed case data. *P=0.005; †P<0.001; ‡P<0.05 vs placebo. CI indicates confidence interval; LS, least squares; and tx, treatment.

Figure 3.

Change in Montreal Cognitive Assessment (MoCA) scores over the course of the study in the intent-to-treat (ITT) population. *P<0.05; **P<0.005 vs placebo. CI indicates confidence interval; LS, least squares; and tx, treatment.